The invention relates to novel arylalkyl- or aryloxylalkyl-substituted oxiranecarboxylic acids, to processes for their preparation, to their use and to medicaments comprising them.
EP 0 046 590 describes hypoglycaemically and hypoketonaemically active phen(alk)oxy-substituted oxiranecarboxylic acids and esters thereof of the general formula A 
in which
R1 is a hydrogen atom, a halogen atom, a 1-4 C-lower alkyl group, a 1-4 C-lower alkoxy group, a nitro group or a trifluoromethyl group,
R2 has one of the meanings of R1,
R3 is a hydrogen atom or a 1-4 C-lower alkyl group,
Y is the grouping xe2x80x94Oxe2x80x94(CH2)mxe2x80x94,
m is 0 or an integer from 1 to 4 and
n is an integer from 1 to 8,
where the sum of m and n is an integer from 2 to 8, and
the salts of the carboxylic acids.
EP 0 231 367 B1 describes the use of the compounds of the general formula A for the prevention and/or treatment of disorders which are caused by an elevated concentration of cholesterol and/or triglyceride in the organism.
DE-A 4 340 879 A1 describes the use of the compounds of the general formula A in the prevention and/or treatment of cardiac insufficiency.
DE-A 3 032 668 describes, inter alia, non-aromatic cycloalkyl(alk)oxy-substituted oxirane-carboxylic acids.
EP 0 283 168 describes phenylalkyl- and phenoxyalkyloxiranecarboxylic acids and esters thereof having 1-2 fluorine substituents in the alkyl chain which are said to act as inhibitors of fatty acid oxidation with a low potential to cause damage to cardiac muscle function.
The invention provides novel arylalkyl- or aryloxyalkyl-substituted oxiranecarboxylic acids or pharmacologically acceptable salts thereof of the general formula I 
in which
Ar is a substituted phenyl radical 
xe2x80x83a 1- or 2-naphthyl radical which unsubstituted is substituted by a radical R4 or is a heterocyclic radical Het,
R1 is a hydrogen atom, a halogen atom or a 1-4 C-lower alkyl group,
R2 is one of the groups 
xe2x80x83or a fully or predominantly fluorine-substituted 1-3 C-alkoxy group,
R3 is a hydrogen atom or a 1-4 C-lower alkyl group,
R4 is a hydrogen atom, a 1-4 C-lower alkyl group, an optionally fully or predominantly fluorine-substituted 1-3 C-alkoxy group or a halogen atom,
R5 in a 1-4 C-lower alkyl group,
Y is the grouping xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94,
n is an integer from 2 to 8 and
Het is a heterocyclic ring, which preferably has 5 members and is selected from the group consisting of thiophene, thiazole, isothiazole, pyrrole and, particularly preferably, pyrazole, and which may carry 1 or 2 identical or different substituents R1,
where the chain xe2x80x94(CH2)nxe2x80x94 may optionally be interrupted by a xe2x80x94CH(CH3)xe2x80x94 or xe2x80x94C(CH3)2xe2x80x94 unit, and the salts of the corresponding carboxylic acids (R3xe2x95x90H).
The 1-4 C-lower alkyl radicals can be straight-chain or branched. Straight-chain alkyl radicals are, for example, the methyl, ethyl, n-propyl and the butyl radical, of which those having 1 to 2 carbon atoms are preferred. Branched alkyl radicals are, for example, the isopropyl, isobutyl and the sec-butyl radical, of which that having 3 carbon atoms is preferred. Suitable alkyl radicals of lower alkoxy groups are both straight-chain and branched lower alkyl groups. A preferred lower alkyl group is the methoxy group. Suitable alkyl radicals in acyl groups are both straight-chain and branched lower alkyl groups, of which the methyl group and the tert-butyl group are preferred.
Halogen atoms are fluorine, chlorine and bromine atoms, of which fluorine and, in particular, chlorine, are preferred.
In the substituted phenyl radicals Ar, the substituents R1 and R2 are preferably in the m- or p-position and R1 is preferably a hydrogen atom.
Among the fully or predominantly fluorine-substituted 1-3-C-alkoxy groups, preference is given to the trifluoromethoxy, the 2,2,2-trifluoroethoxy, the 1,1,2,2-tetrafluoroethoxy group and in particular to the difluoromethoxy group.
Suitable salts are salts with inorganic and organic bases. Pharmacologically unacceptable salts are converted, by methods known per se, into pharmacologically, i.e. biologically, acceptable salts, which are preferred from among the salts according to the invention. Suitable cations for use for salt formation are, in particular, the cations of the alkali metals, alkaline earth metals or noble metals; however, it is also possible to use the corresponding cations of organic nitrogen bases, such as amines, aminoalcohols, amino sugars, basic amino acids, etc.
Examples which may be mentioned are salts of lithium, sodium, potassium, magnesium, calcium, aluminium, ethylenediamine, dimethylamine, diethylamine, morpholine, piperidine, piperazine, N-lower alkyl piperazine (for example N-methylpiperazine), methycyclohexylamine, benzylamine, ethanolamine, diethanolamine, triethanolamine, tris-(hydroxymethyl)-aminomethane, 2-amino-2-methylpropanol, 2-amino-2-methyl-1,3-propanediol, glucamine, N-methylglucamine, glucosamine, N-methylglucosamine, lysine, ornithine, arginine, quinoline.
The arylalkyl- or aryloxyalkyloxiranecarboxylic acids of the general formula I according to the invention have a chiral centre. Accordingly, the invention includes both the racemates and the enantiomers -and mixtures thereof. For racemate separation of the carboxylic acids, particular preference is given to using salts with optically active bases, such as cinchonidine or dehydroabietylamine.
The compounds according to the invention have useful pharmacological properties which make them. They have hypoglycaemic and lipid-lowering action and improve the efficacy of insulin in the treatment of insulin-resistant conditions, such as, for example, in the case of metabolic syndrome and, in particular, diabetes type 2.
They are superior to the known oxiranecarboxylic acids of the prior art in the following manner:
a) they are distinguished by a therapeutic index which is significantly better under certain conditions in the manner that the increases of liver enzymes (transaminases) which occur in individual type 2-diabetics occur to a considerably lesser extent, if at all,
b) they have superior action with respect to increasing the effect of insulin in insulin-resistant conditions,
c) they are metabolized more quickly and do not form any long-lasting metabolites.
Owing to their advantageous and superior efficacy, the compounds of the general formula I according to the invention and the pharmacologically acceptable salts are suitable for the treatment and prophylaxis of disorders which are caused by disturbances of glucose and lipid metabolism, in human and veterinary medicine.
They are employed, for example, for treating prediabetic conditions; for the treatment and prevention of the manifestation of diabetes type 2 and of all pathological conditions which are associated with pathological insulin resistance; for the treatment and prevention of the manifestation of all pathological conditions with pathologically elevated production of ketone bodies; for the treatment and prevention of the manifestation of all pathological conditions which are caused by elevated cholesterol and/or triglyceride concentrations in the blood (hyperlipidaemia, arteriosclerosis, coronary heart disease)
The invention also provides the compounds according to the invention for use in the treatment and prophylaxis of the disorders mentioned.
The invention furthermore provides medicaments comprising one or more arylalkyl- or aryloxyalkyloxiranecarboxylic acids of the general formula I 
in which
Ar is a substituted phenyl radical 
xe2x80x83a 1- or 2-naphthyl radical which is substituted by a radical R4 or is a heterocyclic radical Het,
R1 is a hydrogen atom, a halogen atom or a 1-4 C-lower alkyl group,
R2 is one of the groups 
xe2x80x83or a fully or predominantly fluorine-substituted 1-3 C-alkoxy group,
R3 is a hydrogen atom or a 1-4 C-lower alkyl group,
R4 is a hydrogen atom, a 1-4 C-lower alkyl group, an optionally fully or predominantly fluorine-substituted 1-3 C-alkoxy group or a halogen atom,
R5 is a 1-4 C-lower alkyl group,
Y is the grouping xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94,
n is an integer from 2 to 8 and
Het is a heterocyclic ring, which preferably has 5 members and is selected from the group consisting of thiophene, thiazole, isothiazole, pyrrole and, particularly preferably, pyrazole, and which may carry 1 or 2 identical or different substituents R1,
where the chain xe2x80x94(CH2)nxe2x80x94 may optionally be interrupted by a xe2x80x94CH(CH3)xe2x80x94 or xe2x80x94C(CH3)2xe2x80x94 unit, and the pharmacologically acceptable salts of the carboxylic acids (R3xe2x95x90H) with inorganic or organic bases.
Moreover, the invention provides the use of the compounds according to the invention for preparing medicaments for controlling the disorders mentioned.
The medicaments are prepared by processes known per se. As medicaments, the compounds according to the invention are employed either as such or, if appropriate, in combination with suitable pharmaceutical excipients. If the pharmaceutical preparations comprise pharmaceutical excipients in addition to the active compounds, the active compound content of this mixture is from 1 to 95, preferably from 10 to 85% (w/w) of the total mixture. The medicaments are formulated in suitable doses, for example for oral or parenteral (intravenous, intramuscular) administration. The daily dose for oral administration in humans is generally between 0.1 and 30, preferably between 0.3 and 15, in particular between 0.6 and 3 mg/kg of body weight. The dosage for parenteral treatment is between 0.3 and 1 mg of active compound/kg of body weight.
The pharmaceutical preparations preferably comprise the active compounds according to the invention and non-toxic, pharmaceutically acceptable pharmaceutical excipients which are employed as additive or diluent in solid, semi-solid or liquid form or as coating material, for example in the form of a capsule, a tablet coating, a bag or another container for the therapeutically active component. An excipient may serve, for example, to mediate the uptake of the medicament by the body, as formulation auxiliary, as sweetener, as taste corrigent, as colorant or as preservative.
In addition to the compounds of the general formula I, according to the invention in which the substituents are as defined above, and/or their salts, the pharmaceutical preparations may furthermore comprise one or more pharmacologically active components of other medicament groups, such as antidiabetics (sulphonamides, sulphonylureas, thiazolidinediones, etc.) or hypolipidemics (nicotinic acid and its derivatives, clofibrate, HMG-CoA reductase inhibitors).
The compounds according to the invention are prepared by processes known per se. Detailed instructions for preparing the principal compound class are described in EP 0046 590 equivalent to Eistetter et al., U.S. Pat. No. 4,337,267, the disclosure of which is incorporated herein by reference mentioned at the outset, which is incorporated into the disclosure of this application with respect to process technique. These procedures can be applied, in analogous process steps, to the novel compounds according to the invention. For the person skilled in the art, it is possible without problems to introduce the novel meanings according to the invention for the radical R2, which are chemically customary per se, in comparison to the European Application mentioned, by numerous standard methods.
Here, the compounds of the general formula I are usually obtained in the form of racemic mixtures, which are separated into the enantiomers using known methods. For example, the racemate is converted into diasteromers using an optically active resolving agent, and the diastereomers are subsequently separated by selective crystallization and converted into the corresponding optical isomers. Optically active resolving agents which can be employed are, for example, optically active bases, such as 1- and d-1-phenylethylamine, cinchonidine or d-ephedrine, which are used to prepare salts of the acids of the general formula I, or optically active alcohols, such as borneol or menthol, which are used to prepare esters from the acids of the general formula I. Racemate resolution of the acids using dehydroabiethylamine as salt former has been found to be particularly suitable.